Ligand-assisted, copper-catalyzed enantioselective benzylic amination

Article abstract of DOI:10.1016/j.tetlet.2010.01.118

Several classes of ligands, including α-amino acids, diamines, diphosphines, bis-oxazolines, and diimines, support efficient copper-catalyzed amination of benzylic hydrocarbons by anhydrous chloramine-T. Catalysts derived from homochiral ligands, particularly chiral diimines, effect aminosulfonation with low to moderate enantioselectivity.

Full text of DOI:10.1016/j.tetlet.2010.01.118

Tetrahedron Letters 51 (2010) 1815–1818
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Ligand-assisted, copper-catalyzed enantioselective benzylic amination
*
Dipti N. Barman, Kenneth M. Nicholas
Department of Chemistry and Biochemistry, University of Oklahoma, Norman, OK 73019, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Several classes of ligands, including a-amino acids, diamines, diphosphines, bis-oxazolines, and diimines,
Received 20 January 2010
Revised 28 January 2010
Accepted 29 January 2010
Available online 4 February 2010
support efficient copper-catalyzed amination of benzylic hydrocarbons by anhydrous chloramine-T. Cat-
alysts derived from homochiral ligands, particularly chiral diimines, effect aminosulfonation with low to
moderate enantioselectivity.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Hydrocarbon amination
Ligand-assisted copper catalysis
Enantioselective
Chloramine-T
The synthetic potential of the direct N-functionalization of
hydrocarbons has stimulated intense interest in the discovery of
transition metal-promoted C–H insertion reactions of nitrenoid
precursors with hydrocarbons.1 Many of the recent developments
in this area have focused on benzylic substrates, employing imi-
do-iodinanes (ArI = NTs), chloramine-T (TsNNaCl), or aryl azides
as aminating agents in conjunction with various metal catalysts,
including those of rhodium,2 ruthenium,3 cobalt,4 manganese,5 sil-
ver,6 gold,7 palladium,8 iron,9 copper,10 and zinc.11 Among these,
the reactions catalyzed by dinuclear Rh-complexes are the most
developed and can effect intra- and some intermolecular amina-
tions of a variety of activated and non-activated C–H bonds.2 Pro-
gress toward the challenging goal of enantioselective C–H
amination has been limited, with the most notable success coming
in intramolecular L*2Rh2- and Ru(pybox*)-catalyzed reactions,2c,3c
reagent-based [ArS*(O)(NSO2Ar)NH2] Rh-catalyzed intermolecular
reactions,2d and (salen*)Mn-catalyzed intermolecular reactions of
benzylic substrates.5
Our group has sought the development of new catalytic amina-
tion reactions that employ inexpensive and convenient N-reagents
and catalysts.12 We reported recently that benzylic substrates could
be efficiently amidated by inexpensive anhydrous chloramine-T
with commercial [Cu(CH3CN)4]Z as the catalyst.10d In order to con-
trol catalyst activity and selectivity, for example, to achieve enantio-
selective C–H aminations, it is necessary to identify ligand partners
for the metal center that will support catalysis. Although a number
of ligated copper catalysts have been reported for enantioselective
olefin aziridination,13 examples of ligand-assisted catalytic C–H
aminations are rare10b,f and untested for stereoselectivity. We report
herein our findings of L-assisted, Cu-catalyzed oxidative amination
reactions and efforts to effect enantioselective variants.
To screen ligands for their effect on the activity of Cu-catalyzed
amination, 4-ethylanisole was selected as a test substrate since its
amination by chloramine-T (TsNNaCl) catalyzed by ‘ligandless’
Cu(CH3CN)4PF6 (10 mol %) is slow at 20 °C (12 h, CH3CN, <5% yield
of 4-MeOC6H4CH(NHTs)CH3 (1)). Corresponding reactions were
conducted in the presence of representative ligand types under
Table 1
Effect of ligands on the amination of 4-ethylanisolea
Ligand
Rxn time (h)
Yield of 1b (%)
None
P(OMe)3
PPh3
Ph2PCH2CH2PPh2
Me2N(CH2)2NMe2
Phenanthroline
S-Proline
S-Lysine
S-Histidine
A1
12
16
16
16
12
12
12
12
12
12
12
6
5
68
62
66
52
77
45
67
67
20
56
74
81
88
A2
A3
A4
A5
6
6
a
See Ref. 14 for procedure.
Yield determined by NMR integration of reaction mixture; TsNH2 is the only
b
* Corresponding author. Tel.: +1 405 325 3696; fax: +1 405 325 6511.
E-mail address: knicholas@ou.edu (K.M. Nicholas).
detected by-product.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.01.118

1816
D. N. Barman, K. M. Nicholas / Tetrahedron Letters 51 (2010) 1815–1818
the same conditions (1:1, Eq. 1), including
a-amino acids, phos-
Having established the ability of several ligated-Cu systems to
effectively catalyze benzylic amination by chloramine-T, homochi-
ral ligands were selected and tested for their ability to effect enan-
tioselective aminations of prochiral benzylic substrates. All
reactions were conducted under the previously established condi-
tions with 1:1 L*/Cu. The optical purity of the isolated amination
products was assayed polarimetrically and/or by chiral HPLC and
the results are shown in Table 3. With 4-ethylanisole as substrate
phines, phosphites, diamines, and diimines, and the yield of sulfon-
amide 1 determined by NMR and/or isolation. The results are
summarized in Table 1. Moderate to excellent yields are obtained
with several of these ligands, demonstrating ligand-assisted catal-
ysis.14 The accessibility of diverse diimine ligands from primary
diamines and aldehyde building blocks15 facilitated an assessment
of the electronic effects of the ligand on the catalytic activity. Inter-
estingly, the more electron poor the diimine, the higher the reac-
tion rate and yield of 1 (cf. Table 1, A1–A5).
negligible enantioselectivities were observed with the
a-amino
acid ligands, histidine and proline, however, a low but significant
NHTs
[Cu (CH3CN)4] PF6 , L
TsNNaCl
ð1Þ
(1)
MeO
MeO
CH3CN, rt
1
To assess the ligand-assisted reaction’s scope a survey of the
catalytic amination of a set of representative benzylic substrates
was carried out using complexes derived from the nitro-substi-
tuted diimine ligands A5 and A6. The reactions were conducted un-
der the same conditions as established for 4-ethylanisole (CH3CN,
rt, 6–12 h, 0.1 equiv Cu(CH3CN)4PF6/0.1 equiv L). The results are
summarized in Table 2. Several secondary and tertiary benzylic
hydrocarbons were thus aminated with moderate efficiency and
good regioselectivity, with TsNH2 as the only detected by-product.
Catalysts derived from either the mononitro- or dinitro-ligands
were comparably effective. The enhanced activity of the diimine-
based catalysts was again indicated by the room temperature con-
versions of the starting material with the former catalysts versus
the 60–70 °C required for reactions with Cu(CH3CN)4Z. More
impressively, the saturated substrate adamantane, unreactive to
chloramine-T/[Cu(CH3CN)4]Z even at 70 °C,10d was aminated albeit
in modest (unoptimized) yield by the (A6)–copper complex.
enantioselectivity was achieved with the chiral phenanthroline
E.16 Negligible to low stereoinduction was also found in the reac-
tions employing the diimine ligands derived from 1,2-cyclo-
hexyldiamine (A5 and A6) and from binaphthyldiamine (C1).
More substantial enantioselectivities were found employing the
catalyst derived from the biphenyldiamine ligand B2, with 4-ethy-
lanisole, ethylbenzene and indane.
Although the enantioselectivities achieved in the Cu-catalyzed,
L-assisted reactions are not synthetically useful, they strongly sug-
gest that a chiral-Cu complex of a –NTs species, at least in part is
responsible for the C–H insertion and thus may be improved with
more sterically demanding ligands. The modest enantioselectivi-
ties observed may reflect ineffective chirality transfer from the ter-
nary LCu–NTs complex and/or a stepwise process for C–H cleavage
and C–N bond formation. Preliminary results from a mechanistic
study, that is, underway suggest a contribution from the latter. A
full report on this study will be forthcoming.
Y
Y
X
Z
N
X
N
N
Z
X
N
Y
N
Y
Z
X
Z
X
N
X
Y
Y
B1 (X=H; Y,Z=NO2)
B2 (X,Y=NO2; Y=H)
C1 (X,Y=NO2; Z=H)
A1 (X=NMe2; Y,Z=H)
A2 (X,Y,Z=H)
A3 (X,Y=Cl; Z=H)
A4 (X=CF3; Y,Z=H)
A5 (X=NO2; Y,Z=H)
A6 (X,Y=NO2; Z=H)
O
O
N
PPh2
PPh2
N
N
N
E
D
F

D. N. Barman, K. M. Nicholas / Tetrahedron Letters 51 (2010) 1815–1818
1817
Table 2
Table 3 (continued)
Substrate scope of L-assisted, Cu-catalyzed aminationa
Substrate
Ligand
Product
Yieldb (%) ee (%)
Substrate
Ligand
Product
Yieldb (%)
68
NHTs
F
B2
55
66
7d
Indane
28d
Ethylbenzene
A6
NHTs
NHTs
a
b
c
See Ref. 14 for procedure.
Isolated yield; by-product is TsNH2.
Determined polarimetrically.
Reaction in 1,2-dichloroethane showed that same yield and enantioselectivity.
Determined by HPLC on Chiralcel OJ column; 15% i-PrOH/85% hexane eluant.
Indane
A6
66
d
e
NHTs
NHTs
Cumene
Cumene
A5
A6
62
67
Acknowledgment
NHTs
Diphenylmethane
Diphenylmethane
A5
A6
64
65
We are grateful for financial support provided by the National
Science Foundation.
Ph
Ph
NHTs
Supplementary data
Ph
Ph
Ph
Ph
NHTs
Ph
Ph
Supplementary data (procedures and characterizational data for
ligands and products) associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.01.118.
Triphenylmethane
A5
59
Triphenylmethane
Adamantane
A6
A6
62
19
NHTs
Ph
Ph
References and notes
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a
See Ref. 14 for procedure.
Isolated yield; by-product is TsNH2.
b
Table 3
Copper-catalyzed enantioselective aminationa
Substrate
Ligand
Product
Yieldb (%) ee (%)
3c
MeO
4-Ethylanisole S-Histidine
4-Ethylanisole S-Proline
67
45
68
65
88
85
48
84
81
71
68
NHTs
NHTs
NHTs
NHTs
NHTs
NHTs
NHTs
NHTs
NHTs
NHTs
4c
MeO
MeO
MeO
MeO
MeO
MeO
MeO
MeO
MeO
4-Ethylanisole
E
12c
5c
4-Ethylanisole Dd
4-Ethylanisole A5
4-Ethylanisole A6
4-Ethylanisole B1
4-Ethylanisole B1
4-Ethylanisole B2
4-Ethylanisole C1
Ethylbenzene B2
7c
4c
4c
6c
39c, 16d
5c
14. Typical procedure: Commercial Cu(CH3CN)4PF6 (28 mg, 0.073 mmol), the ligand
(0.073 mmol), and 5 mL of dry CH3CN were added to a round-bottomed flask
containing dry molecular sieves (4 Å, ca. 200 mg) under argon. To the
22d
NHTs

1818
D. N. Barman, K. M. Nicholas / Tetrahedron Letters 51 (2010) 1815–1818
well-stirred suspension 4-ethyl anisole (0.10 mL, 0.73 mmol) was added.
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